Breast cancer is one of the most prevalent of all cancers. Significant levels of estrogen receptor (ER) have been detected in more than 60% of human breast cancers whereas, overexpression of erbB-2 has been detected in 25% of breast cancers. In general, the overexpression of erbB-2 correlates with poor prognosis. In ER-positive patients, overexpression of erbB-2 is associated with hormone resistance. To fully appreciate the therapeutic value of ER and erbB-2 in treatment, a clearer understanding of their role and interactions in breast cancer is necessary. Although evidence accumulates to support the relationship between erbB-2 overexpression and poor survival in breast cancer, an understanding of the biological consequences of erbB-2 overexpression that contribute to poor prognosis and hormone resistance remains elusive. The recent discovery of the erbB-2 ligands, gp30 and p75, has allowed us to identify a number of related but distinct biological endpoints which appear responsive to signal transduction through the erbB-2 receptor. Preliminary data from our laboratory suggest that the estrogen and erbB-2 receptors represent alternative pathways of malignant growth and that activation of erbB-2 leads to a more invasive phenotype. These studies also suggest that erbB-2 overexpression may lead to hormone resistance through modulation of ER function. The proposed studies are designed to define the role of ER and erbB-2 in the malignant progression of breast cancer and through this understanding develop more rational strategies for breast cancer treatment. More specifically these studies are designed to: 1, define the mechanisms of ER regulation by erbB-2 ligand(s) and to identify the mechanism of hormone resistance in ER-positive/erbB-2-positive patients; 2, develop anti-erbB-2 treatment strategies using an inhibitory synthetic peptide, RL2; and 3, develop more rational strategies for anti-estrogen and anti- erbB-2 treatment of breast cancer. The proposed studies will initially be conducted using in vitro cell culture systems. Indications regarding treatment efficacy will be tested in nude mice against the appropriate human breast cancer cell lines. Ultimately, these experiments will facilitate the emergence of erbB-2-targeted therapy, as well as, optimization of currently employed anti-estrogen therapy. Promising treatment strategies will be tested in clinical trials.